Human immunodeficiency virus type I (HIV-1) has contributed to an estimated 40 million deaths since it was first recognized in 1981. Currently, over 30 million people worldwide are living with the virus. The development of effective HIV-1 vaccine immunogens that can elicit high titer, potent, and broadly neutralizing antibodies (bnAbs) remains a major challenge.
Entry of HIV-1 into target cells is mediated by binding of highly conserved epitopes on HIV envelope glycoproteins (Env) to a primary cell-surface receptor CD4. Binding of Env to CD4 initiates a series of conformational changes of the Env structure, leading to exposure and/or formation of coreceptor binding sites that are recognized by cell surface co-receptors (e.g. chemokine receptors CCR5 or CXCR4). To evade human immune surveillance, HIV-1 has evolved a variety of strategies, including rapid generation of genetic variants and hiding of conserved epitopes on envelope glycoproteins (Env) by variable loops, heavy glycosylation, oligomerization and conformational masking.
HIV-1 Env-specific antibodies can be categorized into two major groups: the surface domain gp120-specific Abs and the transmembrane domain gp41-specific Abs. Anti-gp120 Abs include CD4 binding site (CD4bs) Abs, CD4-induced (CD41) Abs and Abs against other regions of gp120. These antibodies are believed to act, at least in part, by binding to the exposed Env surface and obstructing the initial interaction between a trimeric array of gp120 molecules on the virion surface and receptor molecules on the target cells (see, e.g., Parren et al., Adv. Immunol., 77, 195-262 (2001); Parren et al., J. Vivol., 72, 3512-3519 (1998); and Ugolini et al., J. Exp. Med., 186, 1287-1298 (1997)).
Although CD4bs Abs (e.g. b12) that bind to the CD4 binding site on gp120 can potently neutralize certain HIV strains, resistant variants emerge quickly and thereby significantly reduce the anti-viral effects of CD4bs Abs. CD4i Abs, the most abundant Abs in Env-immunized and HIV-1-infected individuals, recognize the conserved coreceptor binding site on gp120. Before binding of CD4 to HIV Env, access to the coreceptor binding site by the full length CD4i Abs is sterically hindered. As a result, the full length CD4i Abs can not or only weakly neutralize HIV-1 prior to CD4-binding. In the presence of CD4, CD4i Abs potently and broadly neutralize a variety of clades of HIV-1 primary isolates as well as genetically divergent HIV-2.
Although soluble CD4 (sCD4) can be useful for enhancing neutralization activity of CD4i Abs, it suffers from several major limitations. First, some HIV-1 isolates are CD4-independent. In addition, sCD4 cannot neutralize HIV-1 primary isolates, suggesting that sCD4 may not bind to the native envelope spike on the viral surface of primary isolates. Further, sCD4 has a significantly short serum half-life compared to antibodies. Moreover, there is a concern that CD4 constructs may deplete CD4-positive T cells in vivo.
It is believed that potent broadly neutralizing antibodies (bnAbs) can serve as a promising candidate for prevention and treatment of HIV-1 infection. bnAbs, which are rarely found in HIV-infected individuals, may slow or delay the progression of HIV-1 infection. An estimated 1% natural infections lead to long-term no disease progression without treatment. Among these long-term nonprogressors (LTNPs), about 30% have high titres of bnAbs. Polyclonal antibodies (pAbs) purified from sera of these LTNPs have shown to produce certain desirable treatment effects on HIV-1-infected patients.
However, monoclonal antibodies (mAbs) isolated from LTNPs only exhibited weak or modest neutralizing activity. A mixture of the isolated mAbs did not show neutralization potency and breadth that are comparable to those of the pAbs. Even for a handful of mAbs that exhibit in vitro broadly neutralizing human monoclonal antibodies (bnmAbs), such as anti-gp120 mAbs b12 and 2G12 and anti-gp41 mAbs 2F5 and 4E10, none of them resulted in satisfactory in vivo efficacy in human clinical trials. Furthermore, currently available mAbs such as b12, 2F5, and 4E10 are shown to possess autoimmune reactivity, including binding to self antigens such as dsDNA, cardiolipin, and phosphotidylserine.
Since HIV-1 was first discovered more than two decades ago, conventional vaccine strategies have failed to develop effective vaccine candidates that can elicit potent broadly cross-reactive HIV-1-neutralizing antibodies. There continues to be a pressing need for novel HIV vaccine strategies and compositions that can control the spread of HIV/AIDS pandemic.